Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer.

Academic Journal

Tamura K; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Yu J; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.; Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Hata T; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Suenaga M; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Shindo K; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Abe T; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
MacGregor-Das A; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Borges M; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Wolfgang CL; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.; Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Weiss MJ; Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
He J; Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Canto MI; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.; Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Petersen GM; Health Sciences Research, Mayo Clinic, Rochester, MN 55905.
Gallinger S; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5.
Syngal S; Population Sciences Division, Dana-Farber Cancer Institute, Boston, MA 02215.
Brand RE; Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213.
Rustgi A; Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.; Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.; Pancreatic Cancer Translational Center of Excellence, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.; Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
Olson SH; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10017.
Stoffel E; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.
Cote ML; Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201.
Zogopoulos G; The Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada H3H 2R9.; The Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada H3A 1A3.
Potash JB; Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
Goes FS; Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
McCombie RW; Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
Zandi PP; Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
Pirooznia M; Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
Kramer M; Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
Parla J; Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.; InGenious Targeting Laboratory, Ronkonkoma, NY 11779.
Eshleman JR; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Roberts NJ; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Hruban RH; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Klein AP; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.; Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Goggins M; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; mgoggins@jhmi.edu.; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.; Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.

Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 May 01; Vol. 115 (18), pp. 4767-4772. Date of Electronic Publication: 2018 Apr 18.

English

To evaluate whether germline variants in genes encoding pancreatic secretory enzymes contribute to pancreatic cancer susceptibility, we sequenced the coding regions of CPB1 and other genes encoding pancreatic secretory enzymes and known pancreatitis susceptibility genes ( PRSS1 , CPA1 , CTRC , and SPINK1 ) in a hospital series of pancreatic cancer cases and controls. Variants in CPB1 , CPA1 (encoding carboxypeptidase B1 and A1), and CTRC were evaluated in a second set of cases with familial pancreatic cancer and controls. More deleterious CPB1 variants, defined as having impaired protein secretion and induction of endoplasmic reticulum (ER) stress in transfected HEK 293T cells, were found in the hospital series of pancreatic cancer cases (5/986, 0.5%) than in controls (0/1,045, P = 0.027). Among familial pancreatic cancer cases, ER stress-inducing CPB1 variants were found in 4 of 593 (0.67%) vs. 0 of 967 additional controls ( P = 0.020), with a combined prevalence in pancreatic cancer cases of 9/1,579 vs. 0/2,012 controls ( P < 0.01). More ER stress-inducing CPA1 variants were also found in the combined set of hospital and familial cases with pancreatic cancer than in controls [7/1,546 vs. 1/2,012; P=0.025; odds ratio, 9.36 (95% CI, 1.15-76.02)]. Overall, 16 (1%) of 1,579 pancreatic cancer cases had an ER stress-inducing CPA1 or CPB1 variant, compared with 1 of 2,068 controls ( P < 0.00001). No other candidate genes had statistically significant differences in variant prevalence between cases and controls. Our study indicates ER stress-inducing variants in CPB1 and CPA1 are associated with pancreatic cancer susceptibility and implicate ER stress in pancreatic acinar cells in pancreatic cancer development.
Competing Interests: Conflict of interest statement: M.G., A.P.K., and R.H.H. have received royalties for the licensing of PALB2 as a pancreatic cancer susceptibility gene. S.S. is a consultant to Myriad Genetics, Inc. R.W.M. has participated in Illumina-sponsored meetings over the past 4 y and received travel reimbursement and an honorarium for presenting at these events. Illumina had no role in decisions relating to the study/work to be published, data collection and analysis of data, and the decision to publish. R.W.M. has participated in Pacific Biosciences-sponsored meetings over the past 3 y and received travel reimbursement for presenting at these events. R.W.M. is a founder and shared holder of Orion Genomics, which focuses on plant genomics and cancer genetics. R.W.M. is a scientific advisory board member for RainDance Technologies, Inc. None of the other authors has any conflicts of interest to declare.